Pei Xingyao, Ma Shuhui, Hong Liang, Zuo Zonghui, Xu Gang, Chen Chun, Shen Yao, Liu Dingkuo, Li Cun, Li Daowen
Open Fund of Key Laboratory of Smart Breeding (Co-construction By Ministry and Province), Ministry of Agriculture and Rural Affairs, Tianjin Agricultural University, Jinjing Road No.22, Xiqing District, Tianjin 300392, China; Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Jinjing Road No.22, Xiqing District, Tianjin 300392, China.
Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Jinjing Road No.22, Xiqing District, Tianjin 300392, China.
Food Chem Toxicol. 2025 Feb;196:115166. doi: 10.1016/j.fct.2024.115166. Epub 2024 Nov 29.
T-2 toxin, a potent environmental pollutant, has been proved to stimulate neuroinflammation, while the connection between T-2 toxin and pyroptosis remain elusive. Dimethyl fumarate (DMF), recently identified as a neuroprotectant and pyroptosis inhibitor, has potential therapeutic applications that are underexplored. Based on present study in vitro and vivo, we demonstrated that T-2 toxin induced the activation of NLRP3-Caspase-1 inflammasome in hippocampal neurons. In addition to proinflammatory mediator overexpression, gasdermin D (GSDMD)-dependently pyroptosis in the mouse hippocampal neuron cell line (HT22) treated by T-2 toxin was determined in our study. Moreover, the palliative effect of knockdown sequence of high mobility group B1 protein (HMGB1) provided more details for T-2 toxin-initiated pyroptosis. Importantly, we confirmed that DMF, as a novel inhibitor of GSDMD, could alleviate pyroptosis induced by T-2 toxin in an GSDMD targeting manner. In summary, our studies exposed the evidence that T-2 toxin could induce NLRP3 inflammasome activation and hippocampal neuronal pyroptosis. More notably, DMF was turn out to be a critical executioner for attenuating GSDMD-mediated pyroptosis. Our data found a new function of DMF and suggested a novel therapy strategy against mycotoxin-triggered neuronal inflammation, which leads to varieties of neurological diseases.
T-2毒素是一种强效环境污染物，已被证明会刺激神经炎症，而T-2毒素与细胞焦亡之间的联系仍不清楚。富马酸二甲酯（DMF）最近被鉴定为一种神经保护剂和细胞焦亡抑制剂，其潜在治疗应用尚未得到充分探索。基于目前的体内外研究，我们证明T-2毒素可诱导海马神经元中NLRP3-半胱天冬酶-1炎性小体的激活。除了促炎介质的过表达外，我们的研究还确定了T-2毒素处理的小鼠海马神经元细胞系（HT22）中gasdermin D（GSDMD）依赖性细胞焦亡。此外，高迁移率族蛋白B1（HMGB1）敲低序列的缓解作用为T-2毒素引发的细胞焦亡提供了更多细节。重要的是，我们证实DMF作为一种新型的GSDMD抑制剂，可以以靶向GSDMD的方式减轻T-2毒素诱导的细胞焦亡。总之，我们的研究揭示了T-2毒素可诱导NLRP3炎性小体激活和海马神经元细胞焦亡的证据。更值得注意的是，DMF被证明是减轻GSDMD介导的细胞焦亡的关键执行者。我们的数据发现了DMF的新功能，并提出了一种针对霉菌毒素引发的神经炎症的新治疗策略，这种炎症会导致多种神经疾病。
